EP1244445A2 - Use of azoles for preventing skin cancer - Google Patents

Use of azoles for preventing skin cancer

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Publication number
EP1244445A2
EP1244445A2 EP00983295A EP00983295A EP1244445A2 EP 1244445 A2 EP1244445 A2 EP 1244445A2 EP 00983295 A EP00983295 A EP 00983295A EP 00983295 A EP00983295 A EP 00983295A EP 1244445 A2 EP1244445 A2 EP 1244445A2
Authority
EP
European Patent Office
Prior art keywords
azoles
radiation
skin cancer
skin
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP00983295A
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German (de)
French (fr)
Other versions
EP1244445B1 (en
Inventor
Bernward Fladung
Harald Enzmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
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Bayer AG
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Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP1244445A2 publication Critical patent/EP1244445A2/en
Application granted granted Critical
Publication of EP1244445B1 publication Critical patent/EP1244445B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of azoles for the prevention of skin cancer caused by radiation.
  • UN rays are classified into UN-A rays (320-400 nm, UN-AI: 340-400 nm, UN-A-II: 320-340 nm) or UN-B rays (280-320 nm ) assigned.
  • UN-A rays 320-400 nm
  • UN-AI 340-400 nm
  • UN-A-II 320-340 nm
  • UN-B rays 280-320 nm
  • UN rays can cause acute and chronic skin damage, the type of damage depending on the wavelength of the radiation.
  • the UN-B radiation can cause sunburn (erythema) and severe skin burns. Reductions in enzyme activities, disturbances in the D ⁇ S structure and changes in the cell membrane as a damaging effect of the UN-B
  • UV-A rays penetrate into the deeper layers of the skin and can accelerate the aging process of the skin there.
  • the shorter-wave UV-A-II radiation additionally increases the formation of sunburn.
  • UV-A radiation can trigger phototoxic or photoallergic skin reactions.
  • the invention makes it possible, for example, to produce azole-containing sunscreens which prevent the UV-induced development of skin cancer, in particular squamous cell carcinoma, basalioma and malignant melanoma. inhibit or prevent entirely.
  • the invention thus relates to the use of azoles for the production of topical agents for the prevention of radiation-induced skin cancer.
  • Preferred azoles for the prevention of skin cancer correspond for example to the formula
  • R represents a trifluoromethyl, methoxy or o-chloro substituent, cf.
  • Croconazole l- (l- [2- (3-chlorobenzyloxy) phenyl] vinyl) imidazole
  • Clotrimazole l - [(2-chloro-phenyl) -diphenylmethyl] -lH-imidazole
  • Fluconazole 2- (2,4-Difluo ⁇ henyl) -l, 3-bis (lH-l, 2,4-triazol-l-yl) -2-propanol
  • Isocanazole 1 - [2- (2,4-dichloro-henyl) -2 [(2,6-dichloro-henyl) methoxy] ethyl] -l H-imidiazole
  • Itraconazole (+) - 2-sec-butyl-4- [4- (4 - ⁇ [(2R, 4S) -2- (2,4-dichlo ⁇ henyl) -2-
  • agents according to the invention can exist in the commonly used forms of application, i.e. e.g. as an oil-in-water or water-in-oil emulsion, as
  • Milk as a lotion, cream, aerosol, gel.
  • the agents can include commonly used ingredients such as e.g. Emulsifiers, surface-active compounds, lanolin, petroleum jelly, water, triglycerides of fatty acids, polyethylene glycols, fatty alcohols, ethoxylated fatty alcohols, fatty acid esters
  • oils and waxes e.g. isopropyl palmate, isooctyl stearate, diisopropyl adipate, etc.
  • natural or synthetic oils and waxes e.g. titanium dioxide, zinc oxide, pearlescent pigments, color pigments
  • thickeners e.g. hydroxyethyl cellulose, bentonite etc.
  • preservatives UV absorbers, moisturizers, Contain silicone oils, vitamins, glycerin, ethyl alcohol, perfume oils.
  • the azoles are generally used in amounts of 0.3 to 30, preferably 0.5 to 12, in particular 1 to 6,% by weight, based on the finished preparation (composition).
  • the agents according to the invention can be applied to the skin and rubbed in before exposure to radiation. For longer periods of radiation, for example when sunbathing, it is advisable to repeat this process every 2 to 3 hours. After intimate contact with water (bathing, showering), the skin should be completely dried off and rubbed in again with the agent according to the invention if the radiation exposure is to be continued. Effectiveness test

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to azoles which are suitable for the prevention of irradiation-induced skin cancer.

Description

Verwendung von Azolen zur Prävention von Hautkrebs Use of azoles to prevent skin cancer
Die Erfindung betrifft die Verwendung von Azolen zur Prävention von Hautkrebs, der durch Strahlen hervorgerufen wird.The invention relates to the use of azoles for the prevention of skin cancer caused by radiation.
UN-Strahlen werden je nach Wellenlänge in UN-A-Strahlen (320-400 nm, UN-A-I: 340-400 nm, UN-A-II: 320-340 nm) oder UN-B-Strahlen (280-320 nm) eingeteilt. Ganz allgemein gilt: Die schädigende Wirkung der UN-Strahlen auf die menschliche Haut steigt mit sinkender Wellenlänge und steigender Dauer der Exposition.Depending on the wavelength, UN rays are classified into UN-A rays (320-400 nm, UN-AI: 340-400 nm, UN-A-II: 320-340 nm) or UN-B rays (280-320 nm ) assigned. In general, the following applies: The damaging effect of the UN rays on human skin increases with decreasing wavelength and increasing duration of exposure.
UN-Strahlen können akute und chronische Hautschädigungen bewirken, wobei die Art der Schädigung von der Wellenlänge der Strahlung abhängt. So kann die UN-B- Strahlung einen Sonnenbrand (Erythem) bis hin zu schwersten Hautverbrennungen verursachen. Auch Minderungen von Enzymaktivitäten, Störungen der DΝS-Struktur und Veränderungen an der Zellmembran als schädigende Wirkung der UN-B-UN rays can cause acute and chronic skin damage, the type of damage depending on the wavelength of the radiation. The UN-B radiation can cause sunburn (erythema) and severe skin burns. Reductions in enzyme activities, disturbances in the DΝS structure and changes in the cell membrane as a damaging effect of the UN-B
Strahlen sind bekannt. Die UV-A-Strahlen dringen in tiefere Hautschichten ein und können dort den Alterungsprozeß der Haut beschleunigen. Die kürzerwellige UV-A- II-Strahlung verstärkt zusätzlich die Bildung von Sonnenbrand. Außerdem kann die UV-A-Strahlung phototoxische oder photoallergische Hautreaktionen auslösen.Rays are known. The UV-A rays penetrate into the deeper layers of the skin and can accelerate the aging process of the skin there. The shorter-wave UV-A-II radiation additionally increases the formation of sunburn. In addition, UV-A radiation can trigger phototoxic or photoallergic skin reactions.
Sehr häufige und ungeschützte Bestrahlung der Haut mit Sonnenlicht kann in extremen Fällen zu krankhaften Hautveränderungen bis hin zum Hautkrebs fuhren.In extreme cases, very frequent and unprotected exposure of the skin to sunlight can lead to pathological skin changes or even skin cancer.
Bei der Bekämpfung von Tumoren wird oftmals ionisierende Strahlung, ins- besondere Röntgenstrahlung, eingesetzt ("Strahlentherapie"). Dabei wird nicht nur das betroffene Organ, sondern notgedrungen auch die Haut einer Strahlenbelastung ausgesetzt, die schädigend wirkt und im schlimmsten Fall Hautkrebs induzieren kann. Ein Mittel zur Prävention solcher Strahlenschäden wäre überaus wünschenswert. Azole hemmen das Wachstum von normalen und von Krebszellen in vitro und Tumorwachstum in vivo; vgl. L.R. Benzaquen et al., J.A. (1995) Nat. Med. 1, 534 bis 540.When combating tumors, ionizing radiation, in particular X-rays, is often used ("radiation therapy"). Not only the affected organ, but also the skin is inevitably exposed to radiation, which has a damaging effect and, in the worst case, can induce skin cancer. A means of preventing such radiation damage would be highly desirable. Azoles inhibit the growth of normal and cancer cells in vitro and tumor growth in vivo; see. LR Benzaquen et al., JA (1995) Nat. Med. 1, 534 to 540.
Es wurde nun gefunden, dass sich Azole zur Prävention von Strahlen-induziertemIt has now been found that azoles have been used for the prevention of radiation-induced
Hautkrebs eignen. "Strahlen-induziert" im Sinne der Erfindung bedeutet vornehmlich "UV-induziert" und "durch Strahlentherapie induziert".Skin cancer. "Radiation-induced" in the sense of the invention primarily means "UV-induced" and "induced by radiation therapy".
Die Erfindung gestattet es beispielsweise, Azol-haltige Sonnenschutzmittel herzu- stellen, die die UV-induzierte Entstehung von Hautkrebs, insbesondere von Platten- epithelkarzinomen, Basaliomen und malignen Melanomen. hemmen oder ganz verhindern.The invention makes it possible, for example, to produce azole-containing sunscreens which prevent the UV-induced development of skin cancer, in particular squamous cell carcinoma, basalioma and malignant melanoma. inhibit or prevent entirely.
Gegenstand der Erfindung ist also die Verwendung von Azolen zur Herstellung topi- scher Mittel zur Prävention von Strahlen-induziertem Hautkrebs.The invention thus relates to the use of azoles for the production of topical agents for the prevention of radiation-induced skin cancer.
Bevorzugte Azole zur Prävention von Hautkrebs entsprechen beispielsweise der FormelPreferred azoles for the prevention of skin cancer correspond for example to the formula
worin wherein
R einen Trifluormethyl-, Methoxy- oder o-Chlorsubstituenten bedeutet, vglR represents a trifluoromethyl, methoxy or o-chloro substituent, cf.
DE-AS 16 70 976.DE-AS 16 70 976.
Andere bevorzugte Azole umfassen z.B.Other preferred azoles include e.g.
Bifonazol = l-(4-Phenylbenzhydryl)-imidazol Butoconazol = (±) - 1 -[4-(4-Chlorphenyl)-2-[(2,6-dichlorphenyl)thio]butyl]- 1 -Bifonazole = 1- (4-phenylbenzhydryl) imidazole Butoconazole = (±) - 1 - [4- (4-chlorophenyl) -2 - [(2,6-dichlorophenyl) thio] butyl] - 1 -
H-imidazolH-imidazole
Croconazol = l-(l-[2-(3-Chlorbenzyloxy)phenyl]vinyl)imidazol Clotrimazol = l-[(2-Chloφhenyl)-diphenylmethyl]-lH-imidazol Econazol = l-[2-(4-Chlorbenzyloxy)-2-(2,4-dichlθφhenyl)-ethyl]-imidazol Fenticonazol = l-[2-(2,4-Dichlθφhenyl)-2[[4-phenylthio)phenyl]methoxy]- ethyl]- 1 H-imidiazolCroconazole = l- (l- [2- (3-chlorobenzyloxy) phenyl] vinyl) imidazole Clotrimazole = l - [(2-chloro-phenyl) -diphenylmethyl] -lH-imidazole Econazole = l- [2- (4-chlorobenzyloxy) - 2- (2,4-dichlorothenyl) ethyl] imidazole fenticonazole = 1- [2- (2,4-dichlorothenyl) -2 [[4-phenylthio) phenyl] methoxy] ethyl] -1 H-imidiazole
Fluconazol = 2-(2,4-Difluoφhenyl)-l,3-bis(lH-l,2,4-triazol-l-yl)-2-propa- nolFluconazole = 2- (2,4-Difluoφhenyl) -l, 3-bis (lH-l, 2,4-triazol-l-yl) -2-propanol
Isocanazol = l -[2-(2,4-Dichlθφhenyl)-2[(2,6-dichlθφhenyl)methoxy]- ethyl]-l H-imidiazolIsocanazole = 1 - [2- (2,4-dichloro-henyl) -2 [(2,6-dichloro-henyl) methoxy] ethyl] -l H-imidiazole
Itraconazol = (+)-2-sec-Butyl-4-[4-(4-{[(2R,4S)-2-(2,4-dichloφhenyl)-2-Itraconazole = (+) - 2-sec-butyl-4- [4- (4 - {[(2R, 4S) -2- (2,4-dichloφhenyl) -2-
( 1 H, 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3-dioxolan-4-yl-methoxy]- phenyl}-piperazino)-phenyl]-2,4-dihydro-3H-l,2,4-triazol-3-on(1 H, 1, 2,4-triazol-1-ylmethyl) - 1, 3-dioxolan-4-yl-methoxy] - phenyl} -piperazino) -phenyl] -2,4-dihydro-3H-1,2 , 4-triazol-3-one
Ketoconazol (+)-l-Acetyl-4-{4-[2α-(2,4-dichlθφhenyl)-2ß-(l- imidazolylmethyl)-l,3-dioxolan-4ß-ylmethoxy]-phenyl}- piperazinKetoconazole (+) - l-acetyl-4- {4- [2α- (2,4-dichloro-phenyl) -2ß- (l-imidazolylmethyl) -l, 3-dioxolan-4ß-ylmethoxy] phenyl} - piperazine
Miconazol (+)- 1 -[2-(2,4-Dichlorbenzyloxy)-2-(2,4-dichloφhenyl)-ethyl]- l H-imidazolMiconazole (+) - 1 - [2- (2,4-dichlorobenzyloxy) -2- (2,4-dichlorophenyl) ethyl] - 1 H-imidazole
Omoconazol (Z)-l-[2-[2-(4-Chloφhenoxy]-2-(2,4-dichlθφhenyl)-l - methylethenyl]-lH-imidazolOmoconazole (Z) -l- [2- [2- (4-chloro-phenoxy] -2- (2,4-dichloro-phenyl) -l-methylethenyl] -IH-imidazole
Oxiconazol (Z)- 1 -(2,4-dichlθφhenyl)-2-( 1 H-imidazol- 1 -yl)ethanon-0-Oxiconazole (Z) - 1 - (2,4-dichloro-phenyl) -2- (1 H-imidazole-1 -yl) ethanone-0-
[(2,4-dichloφhenyl)methyl]oxim[(2,4-dichloφhenyl) methyl] oxime
Sertaconazol (±)- 1 -[2,4-Dichlor-ß-[(7-chlorbenzol[b]thien-3-yl)methoxy]- phenethyl]imidiazolSertaconazole (±) - 1 - [2,4-dichloro-ß - [(7-chlorobenzene [b] thien-3-yl) methoxy] phenethyl] imidiazole
Sulconazol l-[2-[[(4-Chlθφhenyl)methyl]thio]-2-(2,4- dichlθφhenyl)ethyl]- 1 H-imidazolSulconazole l- [2 - [[(4-Chlθφhenyl) methyl] thio] -2- (2,4-dichlθφhenyl) ethyl] - 1 H-imidazole
Terconazol eis- 1 -[4-[[2-(2,4-Dichlθ henyl)-2-( 1 H- 1 ,2,4-triazol- 1 - ylmethyl)- l ,3-dioxolan-4-yl]methoxy]phenyl]-4-(l- methylethyl)piperazin Tioconazol = (+)- 1 -[2-(2-Chlor-3-thienylmefhoxy)-2-(2,4-dichlθφhenyl)- ethyl]-l H-imidazolTerconazole ice-1 - [4 - [[2- (2,4-dichlorohenyl) -2- (1 H- 1, 2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -4- (1-methylethyl) piperazine Tioconazole = (+) - 1 - [2- (2-chloro-3-thienylmefhoxy) -2- (2,4-dichloro-phenyl) ethyl] -l H-imidazole
Die erfindungsgemäßen Mittel können in den üblicherweise verwendeten Anwen- dungsformen vorliegen, d.h. z.B. als Öl-in-Wasser- oder Wasser-in-Öl-Emulsion, alsThe agents according to the invention can exist in the commonly used forms of application, i.e. e.g. as an oil-in-water or water-in-oil emulsion, as
Milch, als Lotion, Creme, Aerosol, Gel.Milk, as a lotion, cream, aerosol, gel.
Die Mittel können üblicherweise verwendete Bestandteile, wie z.B. Emulgatoren, grenzflächenaktive Verbindungen, Lanolin, Vaseline, Wasser, Triglyceride von Fett- säuren, Polyethylenglykole, Fettalkohole, ethoxylierte Fettalkohole, FettsäureesterThe agents can include commonly used ingredients such as e.g. Emulsifiers, surface-active compounds, lanolin, petroleum jelly, water, triglycerides of fatty acids, polyethylene glycols, fatty alcohols, ethoxylated fatty alcohols, fatty acid esters
(z.B. Isopropylpalmiat, Isooctylstearat, Adipinsäurediisopropylester usw.), natürliche oder synthetische Öle und Wachse, Pigmente (z.B. Titandioxid, Zinkoxid, Perglanz- pigmente, Farbpigmente), Verdickungsmittel (z.B. Hydroxyethylcellulose, Bentonit usw.), Konservierungsstoffe, UV-Absorber, Feuchtigkeitsmittel, Siliconöle, Vita- mine, Glycerin, Ethylalkohol, Parfumöle enthalten.(e.g. isopropyl palmate, isooctyl stearate, diisopropyl adipate, etc.), natural or synthetic oils and waxes, pigments (e.g. titanium dioxide, zinc oxide, pearlescent pigments, color pigments), thickeners (e.g. hydroxyethyl cellulose, bentonite etc.), preservatives, UV absorbers, moisturizers, Contain silicone oils, vitamins, glycerin, ethyl alcohol, perfume oils.
Die Azole werden im allgemeinen in Mengen von 0,3 bis 30, vorzugsweise 0,5 bis 12, insbesondere 1 bis 6 Gew.-%, bezogen auf die fertige Zubereitung (Mittel), eingesetzt.The azoles are generally used in amounts of 0.3 to 30, preferably 0.5 to 12, in particular 1 to 6,% by weight, based on the finished preparation (composition).
Die erfindungsgemäßen Mittel können vor der Strahlenexposition auf die Haut aufgetragen und eingerieben werden. Bei längerer Bestrahlungsdauer, z.B. beim Sonnenbaden, empfiehlt es sich, diesen Vorgang jeweils nach 2 bis 3 Stunden zu wiederholen. Nach innigem Kontakt mit Wasser (Baden, Duschen) sollte die Haut vollständig abgetrocknet und mit dem erfindungsgemäßen Mittel erneut eingerieben werden, falls die Strahlenexposition fortgesetzt werden soll. Test der WirksamkeitThe agents according to the invention can be applied to the skin and rubbed in before exposure to radiation. For longer periods of radiation, for example when sunbathing, it is advisable to repeat this process every 2 to 3 hours. After intimate contact with water (bathing, showering), the skin should be completely dried off and rubbed in again with the agent according to the invention if the radiation exposure is to be continued. Effectiveness test
Induktion von Hauttumoren durch UV-Bestrahlung und deren Verminderung an transgenen Mäusen:Induction of skin tumors by UV radiation and their reduction in transgenic mice:
Gruppe 1 : UN-Exposition + gegebenenfalls SonnenschutzGroup 1: UN exposure + sun protection if necessary
Gruppe 2: UN-Expositionen + Azol + gegebenenfalls SonnenschutzGroup 2: UN exposures + azole + sun protection if necessary
Endpunkt: Papillome erwartungsgemäß nach 4 bis 12 Wochen (Entwicklung von Karzinomen erfordert ca. 10 Monate)End point: papillomas as expected after 4 to 12 weeks (development of carcinomas takes about 10 months)
Die Resultate der beiden Gruppen zeigen, dass Azole vor UN-induzierten Hauttumoren schützen. The results of the two groups show that azoles protect against UN-induced skin tumors.

Claims

Patentansprüche claims
1. Verwendung von Azolen zur Herstellung von topischen Mitteln zur Prävention von Strahlen-induziertem Hautkrebs.1. Use of azoles for the production of topical agents for the prevention of radiation-induced skin cancer.
2. Verwendung nach Anspruch 1, wonach die Azole aus der Reihe Bifonazol, Butoconazol, Clotrimazol, Croconazol, Econazol, Fenticonazol, Fluconazol, Isoconazol, Itraconazol, Ketoconazol, Miconazol, Omoconazol, Oxiconazol, Sertaconazol, Sulconazol, Terconazol, Tioconazol und deren Mischungen ausgewählt sind. 2. Use according to claim 1, according to which the azoles are selected from the series bifonazole, butoconazole, clotrimazole, croconazole, econazole, fenticonazole, fluconazole, isoconazole, itraconazole, ketoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, mixtures, andazaconazolone, mixtures are.
EP00983295A 1999-12-24 2000-12-12 Use of azoles for preventing skin cancer due to radiation Expired - Lifetime EP1244445B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19963052A DE19963052A1 (en) 1999-12-24 1999-12-24 Topical composition for preventing radiation-induced skin cancer, e.g. due to sunbathing or radiotherapy, containing azole compound such as bifonazole or clotrimazole
DE19963052 1999-12-24
PCT/EP2000/012595 WO2001047505A2 (en) 1999-12-24 2000-12-12 Use of azoles for preventing skin cancer

Publications (2)

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EP1244445A2 true EP1244445A2 (en) 2002-10-02
EP1244445B1 EP1244445B1 (en) 2005-08-31

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CN110917192A (en) * 2018-09-20 2020-03-27 华东师范大学 Application of miconazole in preparation of antitumor drugs
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AR027088A1 (en) 2003-03-12
GT200000218A (en) 2002-06-13
WO2001047505A2 (en) 2001-07-05
ES2246912T3 (en) 2006-03-01
WO2001047505A3 (en) 2002-06-20
AU778835B2 (en) 2004-12-23
EP1244445B1 (en) 2005-08-31
DE19963052A1 (en) 2001-06-28
AU2008501A (en) 2001-07-09
BR0017046A (en) 2002-11-05
CA2395345A1 (en) 2001-07-05
DK1244445T3 (en) 2005-11-07
MXPA02006247A (en) 2003-01-28
CO5251436A1 (en) 2003-02-28
ATE303146T1 (en) 2005-09-15
DE50011084D1 (en) 2005-10-06
NZ519731A (en) 2004-06-25
US20020193384A1 (en) 2002-12-19
JP2003518490A (en) 2003-06-10

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